1. Field of the Invention
The invention relates to a method of treating gastrointestinal ulcer disease in an animal comprising administering chemical inhibitors of the activities of enzymes that hydrolyze proteins, generically proteinase inhibitors.
2. Description of the Background Art
Nonspecific ulcers in the stomach and duodenum, commonly but inaccurately referred to as "peptic ulcers," affect about 10% of the population of the United States at least once in a lifetime. Gastroenterology 69:166-174 (1975).
Drug-induced (iatrogenic) ulcers are even more common. A large proportion of chronic users of aspirin and nonsteroidal anti-inflammatory drugs (e.g., patients with rheumatoid arthritis and osteoarthritis, and healthy people aiming for the prevention of disease) are affected by drug-induced ulcers in a dose- and time-dependent manner. Lanza, F.L., et al., Amer. J. Gastroenterol. 80:767-769 (1985); Lorenz, R.L., et al., Lancet 1:1261-1264 (1984).
"Ulcer disease," which is a more accurate designation than "peptic ulcer," is a mass disorder because, just as in cardiovascular diseases and cancer, it affects a large segment of the population and its mechanism(s) of development is (are) poorly understood. It is now clear that ulcer disease is a complex disorder that is multifactorial and pluricausal in origin. Brooks, F.P., in Peptic Ulcer Disease: Contemporary Issues in Gastroenterology, Brooks, F.P., et al., eds., Churchill-Livingston, New York, 1985, 145-151; Szabo, S., Laboratory Investigations 51:121-147 (1984). The multifactorial etiology and pathogenesis imply that it is unrealistic to expect a complete healing or a preventive effect from highly specific drugs that affect only one component in this complex chain of events. It is thus not surprising that after cessation of treatment with even the currently most potent antisecretory agent (the H.sub.2 receptor antagonists such as cimetidine), the recurrence rate of chronic duodenal ulcers is 40-60% a year. Thomas, J.M., et al., Clin. Gastroenterol. 13:501-541 (1984). Novel drugs which affect more than one element in the pathogenesis of ulcer disease are thus realistically expected to have a more profound effect on ulcer healing and recurrence than presently available anti-ulcer drugs. "Future research must address the different etiologies of gastric and duodenal ulcers and other acid-peptic conditions, as well as attempting to cure the disease, rather than simply heal the ulcer." Garner, A., Scand. J. Gastroenterol. 21, Suppl. 125, 203-210 (1986).
Gastric cytoprotection is a recently developed concept of ulcer treatment that attempts to cure the disease, rather than attack the symptoms. This concept has resulted in the development of new compounds that protect the gastric mucosa. As originally defined, gastric "cytoprotection" referred to several specific modalities that prevent or treat hemorrhagic gastric erosions without inhibiting acid secretion. Examples of these specific modalities include: the prostaglandins (Miller, T.A., Amer. J. Physiol. 245:G601-623 (1983)); sulfhydryl group-containing drugs that protect animals from ethanol-induced gastric erosions (Szabo, S., et al., Science 214:200-202 (1981)); and certain other agents.
Additional evidence of the involvement of sulfhydryl groups in gastric "cytoprotection" is provided by reports that the protection afforded by prostaglandins and sulfhydryls (Szabo, S., et al., Science supra at 201); Szabo, S., Klin. Wochenschr. 64, Suppl. VII, 116-122 (1986)), diethylmaleate (Dupuy, D., et al., Digestion 31:165 (1985)), polyamines (MiZui, T., et al., Japan J. Pharmacol. 33:939-945 (1983)), and sodium salicylate (Ezer, E., Digestion 31:168 (1985)) can be counteracted by the irreversible sulfhydryl blocker, N-ethylmaleimide. Further, it has been reported (Dupuy, D., et al., Gastroenterology 91:966-977 (1986)) that divalent heavy metal ions that oxidize or bind to sulfhydryl groups (Friedman, M., The Chemistry and Biochemistry of the Sulfhydryl Groups in Amino Acids, Oxford: Pergamon, 1973, 25-39) protect animals against ethanol-induced gastric mucosal erosions.
More recently, cytoprotective or gastroprotective drugs are being classified more generically as agents with unknown or multiple (e.g., prosecretory effects for bicarbonate or mucus, vasoprotection, etc.) mechanisms of action. Weinstein, W., Drug Therapy, Suppl. 23-27 (1985); Szabo, S., Gastroenterology 88:228-236 (1984); Szabo, S., et al., Gastroenterology 91:966-974 (1986). The most important practical benefit of the concept of gastric cytoprotection is that it stimulates a focus on novel types of antiulcer agents, i.e., drugs that exert gastroprotective or enteroprotective effects by multiple mechanisms of action, without suppressing normal body functions such as gastric and enzyme secretion. The subject matter of the present invention relates to such unique drugs.